The proposal addressees lentiviral vaccination strategies using the macrophage tropic lentivirus caprine arthritis-encephalitis virus (CAEV), specifically cytokine modulation of Th lymphocyte priming initiated by immunization with plasmid DNA encoding CAEV envelope proteins. The research plan is based on well documented murine studies demonstrating that crossregulatory cytokines specify the differentiation of Th1 and Th2 lymphocyte subsets at the time of antigen presentation. This principle suggests that antigen specific Th subset responses can be experimentally controlled on an outbred genetic background by cytokine directed priming, a potentially important concept in HIV vaccine design. Thus, the hypothesis to be tested is that expression plasmids encoding caprine interleukin-12 or interferon-gamma will potentiate Th1 responses to immunization with CAEV env expression plasmid, whereas plasmid DNA encoding caprine interleukin-4 will potentiate antigen specific Th2 responses. Anticipated results will allow CAEV challenge experiments to evaluate control of lentivirus replication by polarized Th1 and Th2 responses to envelope antigens.